Project Summary It is well documented that the ability of the brain to undergo plasticity becomes limited in adults. In particular, sensory experience-dependent plasticity of cortical circuits is rather confined to a limited time during development, termed the critical period. Recovery and refinement of sensory processing is therefore difficult in adults. For example, the success rate of speech recognition in artificial cochlear implant patients becomes quite low, if the surgery is done later in life. Hence discovery of mechanisms that can recover adult cortical plasticity is of essence to benefit recovery of hearing or for treating abnormal auditory processing as occurs with tinnitus. We found that temporary visual deprivation is quite effective at producing large-scale plasticity in the adult primary auditory cortex (A1) of mice. Such changes occurred as potentiation of feedforward excitatory synapses from the primary auditory thalamus (MGBv) to layer 4 (L4) as well as L4 to L2/3. This was accompanied by weakening of synapses arising from lateral intracortical sources to L2/3 of A1. In parallel, we also observed refinement of cortical circuits of A1 L4 and L2/3. Collectively, these changes suggest that A1 circuit adapts to allow better processing of bottom-up auditory inputs, which is consistent with our published observation of refinement of A1 L4 neuronal receptive field and lowering of detection threshold in visually deprived mice. In this application, we aim to determine the mechanisms involved in driving adult A1 plasticity with visual deprivation, and whether visual deprivation improves auditory behavior in adults. Based on our observation that visual deprivation induced potentiation of thalamocortical (TC) inputs to A1 L4 requires audition, but no due to changes in the auditory environment, we surmise that there is central adaptation in circuits mediating auditory signals going through the thalamus and the cortex. In particular, we hypothesize that short-term visual deprivation promotes A1 plasticity in adults by regulating inhibitory circuits at the level of thalamus and cortex (Aim 1). The circuit and synaptic adaptation seen in A1 following vision loss accompanied refinement of A1 L4 neural function, and is predicted to enhance auditory function. We will examine how short- term visual deprivation alters auditory behavioral tasks in adults, and investigate whether this is due to changes in A1 neuronal responses and population encoding during auditory tasks using in vivo 2-photon imaging (Aim 2). Results from our proposed study will provide mechanistic understanding on how short-term visual deprivation enables plasticity of adult A1 via regulation of thalamic and cortical circuits, and will provide means to enhance auditory processing in the adult brain that could benefit development of treatment options for enhancing or recovering auditory function as would be needed for better prognosis of artificial cochlear implants. Furthermore, our results can be generalized to provide insights into how cortical circuits adapt to losing major inputs as it may happen during injury, stroke, and neuronal degeneration.